5mei Citations

Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A.

Abstract

Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5 Å crystal structure of the 80S eukaryotic ribosome from S. cerevisiae in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents.

Reviews - 5mei mentioned but not cited (1)

  1. Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective. Pellegrino S, Terrosu S, Yusupova G, Yusupov M. Cancers (Basel) 13 4392 (2021)

Articles - 5mei mentioned but not cited (1)



Reviews citing this publication (4)

  1. Roadblocks and resolutions in eukaryotic translation. Schuller AP, Green R. Nat Rev Mol Cell Biol 19 526-541 (2018)
  2. Along the Central Dogma-Controlling Gene Expression with Small Molecules. Schneider-Poetsch T, Yoshida M. Annu Rev Biochem 87 391-420 (2018)
  3. A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis. Dmitriev SE, Vladimirov DO, Lashkevich KA. Biochemistry (Mosc) 85 1389-1421 (2020)
  4. The Recurring Roles of Chlorine in Synthetic and Biological Studies of the Lissoclimides. Pak BS, Supantanapong N, Vanderwal CD. Acc Chem Res 54 1131-1142 (2021)

Articles citing this publication (16)